This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our goal for this project is to design and synthesize novel peptide and peptido-mimetic inhibitors, specifically targeted against proteases central to the pathogenesis of malaria, schistosomiasis, trypanosomiasis, and hepatitis A. Crystal structures and in some cases homology-based structural models for target proteases are used for computer-graphics based modeling of ligand binding, for database screening of potential inhibitors as well as for analysis of potential binding modes. Optimization of these compounds is aimed at improving specificity, half-life, and diminishing toxicity. Using medicinal chemistry approaches, we have designed and synthesized a wide variety of chemical compounds which include heteroaromatic inhibitors, peptide-based and peptidomimetic inhibitors. In the early years of this project, mass spectrometry has played an important role in chemical characterization of these lead compounds. Proteomic analysis is also important at early stages of target identification, using affinity based probes that target specific functional subclasses of protease activities.